FTO is required for myogenesis by positively regulating mTOR-PGC-1α pathway-mediated mitochondria biogenesis.
FTO is required for myogenesis by positively regulating mTOR-PGC-1α pathway-mediated mitochondria biogenesis.
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DOI：
10.1038/cddis.2017.122
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发表时间：
2017-03-23
影响因子：
9
通讯作者：
Xiao H
中科院分区：
文献类型：
--
作者：
Wang X;Huang N;Yang M;Wei D;Tai H;Han X;Gong H;Zhou J;Qin J;Wei X;Chen H;Fang T;Xiao H
脂肪质量和肥胖相关（FTO）基因的全球生殖系损失导致小鼠脂肪质量和瘦质量的减少。然而，FTO在脂肪形成中的作用已被提出，而在肌肉形成中的作用尚未提出。骨骼肌是人体瘦质量的主要组成部分，其与FTO的生理意义有待明确。在这里，我们通过体外和体内实验评估了FTO对小鼠骨骼肌分化的影响。我们发现FTO在成肌细胞分化过程中表达增加，而FTO沉默抑制成肌细胞分化；此外，骨骼肌fto缺陷小鼠的骨骼肌发育受损。值得注意的是，fto促进的肌分化依赖于其m6A去甲基化酶的活性。机械上，我们发现FTO下调抑制了线粒体的生物发生和能量产生，表现为线粒体质量和线粒体DNA （mtDNA）含量下降，mtDNA编码基因和过氧化物酶体增殖体激活受体γ辅助激活因子1α (PGC-1α)基因表达下调，ATP水平下降。此外，由于FTO的表达影响mTOR的活性，雷帕霉素阻断FTO诱导的PGC-1α转录，以及在成肌细胞分化过程中FTO表达和mTOR磷酸化的平行改变模式，mTOR-PGC-1α通路参与了FTO与肌肉分化之间的联系。总之，我们的研究结果为FTO对骨骼肌分化的贡献提供了第一个证据，并为研究RNA甲基化的生理意义提供了新的见解。
Global germ line loss of fat mass- and obesity-associated (FTO) gene results in both the reduction of fat mass and lean mass in mice. The role of FTO in adipogenesis has been proposed, however, that in myogenesis has not. Skeletal muscle is the main component of body lean mass, so its connection with FTO physiologic significance need to be clarified. Here, we assessed the impact of FTO on murine skeletal muscle differentiation by in vitro and in vivo experiments. We found that FTO expression increased during myoblasts differentiation, while the silence of FTO inhibited the differentiation; in addition, skeletal muscle development was impaired in skeletal muscle FTO-deficient mice. Significantly, FTO-promoted myogenic differentiation was dependent on its m6A demethylase activity. Mechanically, we found that FTO downregulation suppressed mitochondria biogenesis and energy production, showing as the decreased mitochondria mass and mitochondrial DNA (mtDNA) content, the downregulated expression of mtDNA-encoding genes and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) gene, together with declined ATP level. Moreover, the involvement of mTOR-PGC-1α pathway in the connection between FTO and muscle differentiation is displayed, since the expression of FTO affected the activity of mTOR and rapamycin blocked FTO-induced PGC-1α transcription, along with the parallel alteration pattern of FTO expression and mTOR phosphorylation during myoblasts differentiation. Summarily, our findings provide the first evidence for the contribution of FTO for skeletal muscle differentiation and a new insight to study the physiologic significance of RNA methylation.